Proglucagon-derived peptides as therapeutics

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Abstract

Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development. [Abstract copyright: Copyright © 2021 Lafferty, O’Harte, Irwin, Gault and Flatt.]
Original languageEnglish
Article number689678
Pages (from-to)689678
Number of pages29
JournalFrontiers in Endocrinology
Volume12
Early online date18 May 2021
DOIs
Publication statusPublished - 18 May 2021

Bibliographical note

Funding Information:
Research in the authors? laboratories on gut peptide therapeutics has been generously supported over many years by Diabetes UK, European Foundation for the Study of Diabetes, Diabetes Research and Wellness Foundation, Invest Northern Ireland, Northern Ireland Department for Education, and Ulster University Strategic Funding.

Publisher Copyright:
© Copyright © 2021 Lafferty, O’Harte, Irwin, Gault and Flatt.

Keywords

  • Proglucagon
  • Glucagon
  • GLP-1
  • GLP-2
  • oxyntomodulin (Oxm)
  • diabetes
  • Obesity
  • glicentin
  • Multi-agonist

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